Type II diabetes is an international health scourge that affects more than 300 million subjects throughout the world; it is increasing by 10% to 15% per year.
It is a chronic disease defined by too high a concentration of sugar in the blood, which appears when the pancreas does not secrete enough insulin or when the organism uses the insulin it produces incorrectly. In the long term, the hyperglycemia caused by the excessive presence of glucose in the blood causes certain complications, in particular in the eyes, the kidneys, the nerves, the heart, and the blood vessels.
There are two main types of diabetes.
Diabetes known as type I diabetes or insulin-dependent diabetes is characterized by the insufficient secretion of insulin or by its absence. It is rapidly fatal without the daily administration of insulin by subcutaneous injection(s).
Diabetes known as type II diabetes or adult-onset diabetes is due to poor use of insulin by the organism. It represents 90% of the cases of diabetes in the world and principally results from excess weight and lack of physical exercise.
The physiopathology of type II diabetes associates an anomaly in insulin-sensitivity and in insulin-secretion, in particular a large alteration in the early insulin secretion peak.
An element that has recently been determined as the most actively pathogenic and redolent with vascular, cardiac, and organic consequences in type II diabetes is the existence of a postprandial hyperglycemia (PPHG) peak linked to the absence of an early insulin secretion response.
In the healthy adult, the pancreas produces an early insulin peak that is aimed at metabolizing all of the saturating quantity of glucose absorbed in a rapid cumulative manner during a meal. That early insulin peak can smooth out the sudden variations in glycemia during meals as well as the inevitable consecutive postprandial hyperglycemia. As an example, administration to a non-diabetic person of 20 grams (g) of glucose induces, in a reflex manner, an insulin peak of more than 120 micrograms (μg) per liter (L) of blood in the next 10 minutes (min).
In a type II diabetic person, the same test induces a mean insulin peak of only 35 μg/L of blood, i.e. a 71% deficit, and there is a pathological 30 min delay in its appearance.
Because of that absence of an early response in insulin secretion, per- and post-prandial glycemic variations are not regulated and type II diabetics have to tolerate very high levels of postprandial hyperglycemia of more than 2 g/L to 3 g/L that, even if not felt, represent a hidden danger right from the first stages of the disease.
There are currently several approaches for treating type II diabetes, with the aim of obtaining better control and optimization of glycemia in a stabilized manner, so that thresholds of 1.20 g to 1.40 g of glucose per liter of blood are not exceeded, particularly in the postprandial period. At first, type II diabetes is generally treated by diet and weight loss. Next, if necessary, comes treatment with oral antidiabetics possibly associated with insulin therapy in order to maintain near normal glycemia. The aim of the treatment is to reduce mortality, symptoms, and complications associated with diabetes.
Particular examples of known basic antidiabetics that may be mentioned are hypoglycemia-inducing sulfamides including gliclazide, glibenclamide, and hypoglycemia-inducing biguanides including metformin.
Gliclazide is a lipophilic antidiabetic with a molecular weight of 323 daltons (Da), which is insoluble in water and slightly soluble in alcohol. It acts in the pancreas by stimulating secretions from the islets of Langerhans, increasing the secretion of insulin or peptide C, and also has anti-aggregation type hemato-vascular properties. Currently, gliclazide is administered in unit dosages of 30 milligrams (mg) to 80 mg for 80 mg to 160 mg per day orally. It is extensively metabolized by the first hepatic passage and all of its metabolites are free of activity. With 95% binding to plasma carrier proteins, it has a distribution volume of approximately 30 L, with a plasma peak occurring 11 hours (h) to 14 h after ingestion, and a half-life of 10 h to 12 h.
The other sulfamide, glibenclamide, is a lipophilic active principle that is practically insoluble in water and slightly soluble in ethanol. It is capable of inducing hypoglycemia and is a demonstrated cardiovascular protector. Currently, glibenclamide is administered in unit dosages of 2.5 mg to 5 mg, for on average 10 mg/day (to a maximum of 15 mg/day). It is strongly metabolized by the liver, with a late plasma peak, but has an advantageous effect/dose ratio.
Metformin hydrochloride is a standard amphiphilic antidiabetic with a molecular weight of 165 Da; it is soluble in water and slightly soluble in alcohol. It is a cardiovascular protector that does not act on the pancreatic production of insulin but on the hepatic metabolism of sugar and glycogen, as well as on the use of glucose by tissues. Metformin is currently administered in unit dosages of 500 mg and 1000 mg, for 1000 mg to 3000 mg per day, its absorption being 50% to 60%. It is not bound to plasma proteins and has a distribution volume in the range 63 L to 276 L with a long half-life.
However, although said treatments tend to optimize the glycemia of patients with type II diabetes, none of them takes into account or effectively treats the major and constant problem of the postprandial hyperglycemia (PPHG) peak.
In contrast to type I diabetes, where is it possible to associate a slow release insulin, releasing over 24 h and a rapid-release insulin injected before all meals, guaranteeing a per- and post-prandial insulin peak, which can be adapted by and for each patient, hypoglycemia-inducing treatments proposed for type II diabetes cannot be used to regulate postprandial hyperglycemia in order to keep it close to physiological requirements and international health authority recommendations, namely less than 140 mg of glucose per liter of blood (7.8 nanomoles (nmol) per liter).
The drugs currently used for the chronic treatment of type II diabetes, such as metformin-based drugs, which are all administered orally, offer late activity after taking and a pharmacological availability that remains linear. Thus, they are incapable of reducing, at a given time, the sudden and strong appearance of the postprandial hyperglycemia peak.
However, health authority recommendations concerning the treatment of type II diabetes recognize that the variation in glycemia between “fasting glycemia” and “postprandial glycemia” must not be more than 0.2 g/L to 0.3 g/L, i.e. a very reduced range of fluctuation, which is difficult to obtain with currently available pharmacological means, which are all administered orally and some by injection, which makes therapeutic management by patients more complicated.
For this reason, novel therapeutic classes such as alpha-glucosidase inhibitors, glinides, or gliptins (or incretins) have been developed in order to supplement the constant but insufficient regulatory action of such hypoglycemia-inducing/insulin-secreting agents, administered as a base treatment that remain ill-suited to reducing postprandial hyperglycemia peaks.
Said novel molecules include glinides such as mitiglinide or nateglinide, and in particular repaglinide, which is an oral hypoglycemia-inducing agent that binds to the sulfonylurea receptors of beta pancreatic cells and thus causes rapid short term insulin secretion, capable of responding better to an elevating hyperglycemia. Repaglinide, a derivative of benzoic acid, is a lipophilic molecule with a molecular weight of 452.6 administered in a quantity of 1 mg per meal. The drug has to be taken orally 15 min before each meal three times a day in order to provide better postprandial glycemia control. Repaglinide ingested in that manner causes the onset of an insulinotropic response approximately 30 min after taking it, but with a wide inter-individual variability (60%) in its plasma concentration as well as an intra-individual variability (35%), requiring frequent adjustments in posology. Thus, its digestive absorption and above all its first hepatic passage render its therapeutic efficacy random; these elements alter the immediate pharmacological bioavailability in a variable manner. Thus, that treatment is not satisfactory; moreover, glinides have been shown to cause more hypoglycemia and weight gain than conventional treatments of the metformin type, which is logical since metformin has no insulin-secreting activity.
Incretins or gliptins are intestinal hormones liberated by the endocrinal cells of the intestinal epithelium as nutrients arrive. They play a major role in potentializing the effect of glucose on pancreatic cells. GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are the best known. GLP-1 in particular has a strong insulinotropic action in type II diabetic patients. Further, its capacity to stimulate the synthesis of insulin means that it can be used to maintain insulin reserves in beta pancreatic cells. Said effects have been demonstrated by numerous studies carried out in diabetic patients. Even in patients with very high fasting glycemia who no longer respond to conventional hypoglycemia-inducing agents, administering GLP-1 completely normalizes glycemia due to stimulation of the secretion of insulin that is transitional and returns to the base level when normal glycemia is reached. Continuous perfusion of GLP-1 to obese, diabetic patients for a period of 6 weeks causes a reduction in fasting and postprandial glycemia by 4.3 nanomolar (nM) and 5.5 millimolar (mM) respectively. The hemoglobin HbAlC is reduced by 1.3%, with an improvement in sensitivity to insulin and the function of pancreatic beta cells. However, GLP-1 cannot currently be administered orally because of its peptide nature, and using it requires injection. Furthermore, its in vivo half-life is very short, approximately 1 min to 2 min, due to its rapid degradation by a ubiquitous enzyme, dipeptidylpepditase, which renders it impossible to use. Degradation-resistant forms of GLP-1 have been developed, in particular sitagliptin or vildagliptin or even saxagliptin. Vildagliptin is an amphiphilic molecule that is soluble in water and organic solvents and has a molecular weight of 303.99 Da with a bioavailability of approximately 85%. Sitagliptin is an amphiphilic molecule with a molecular weight of 407.314 Da, which is soluble in water and certain organic solvents; it has an absolute bioavailability of the order of 87%. It is bound to plasma proteins and the mean distribution volume in the organism of a single dose of 100 mg of intravenous sitagliptin is approximately 198 L. Saxagliptin has a molecular weight of 315.41 Da and has a bioavailability that varies in the range 50% to 75% of the orally administered dose; this lipophilic molecule has a high organic distribution volume, close to 180 L. Thus, it can be seen that such molecules have very similar characteristics. However, these peptides, while they improve the overall glycemic profile, always in association with other antidiabetic molecules, cannot overcome the essential problem of type II diabetes, namely compensating for the postprandial hyperglycemia (PPHG) peak during the per/postprandial period; their action on this peak is still marginal.
Thus, none of these novel therapeutic classes is satisfactory. They have insufficient efficacy, are expensive, and some cause tolerance problems or require subcutaneous injections, which presents no advantage over a treatment with insulin that is invasive but would be more effective and more appropriate physiologically.
Thus, the treatment of type II diabetes is currently incomplete and falls short of international recommendations regarding reducing the postprandial hyperglycemia peak. Thus, available therapeutic means are still unsuitable, since there are no drugs that can be used by several hundred million ambulatory patients that can currently combat the PPHG peak to keep it within the recommended limits of a maximum glycemia of less than 1.4 g/L throughout the per/postprandial period.
Thus, there is a substantial need for drugs that can treat the sudden, strong appearance of a PPHG peak, responsible for many medium and long term complications, in particular cardiovascular complications, of type II diabetes.